P723: CLINICAL AND MOLECULAR ASSOCIATIONS WITH OUTCOMES IN HIGHER RISK MYELODYSPLASTIC SYNDROMES TREATED WITH HYPOMETHYLATING AGENTS PLUS VENETOCLAX
Authors: Alexandre Bazinet, Sai Prasad Desikan, Ziyi LI, Sangeetha Venugopal, Samuel Urrutia, Guillermo Montalban-Bravo, Koji Sasaki, Kelly Chien, Danielle Hammond, Rashmi Kanagal-Shamanna, Bailey Mirabella, Stephany Hendrickson, Liz Romero, Simona Colla, Irene Ganan-Gomez, Juan Jose Rodriguez-Sevilla, Tapan Kadia, Courtney Dinardo, Naval Daver, Elias Jabbour, Farhad Ravandi, Hagop Kantarjian, Guillermo Garcia-Manero
Journal: HemaSphere (2023)

Background: The combination of a hypomethylating agent (HMA) and venetoclax (VEN) is an emerging treatment in higher risk myelodysplastic syndromes (HR-MDS). Clinical, cytogenetic, and molecular factors associated with outcomes on this novel treatment are not well characterized. Aims: Identify patient and disease characteristics associated with overall response rate (ORR), event-free survival (EFS), and overall survival (OS) in prospective studies of HMA + VEN in HR-MDS. Methods: We pooled patient data from 3 ongoing single-center phase 1/2 studies (NCT04160052, NCT04550442, NCT04655755). Eligibility criteria were a diagnosis of HR-MDS or CMML (IPSS Int-2 or High) and bone marrow blasts > 5%, with or without prior HMA failure (HMA-f, defined as no response after 4 cycles, or progression after response). Responses were assessed by IWG 2006. Univariate and multivariate analyses were performed to identify associations between outcomes and clinical/molecular factors (age, diagnosis [MDS-EB1, MDS-EB2, CMML], blast %, individual cytogenetic findings/mutations seen in at least 3 patients). Factors with a p < 0.20 in univariate analysis (UVA) were retained for the multivariate analysis (MVA) followed by backward selection until all factors were significant at p < 0.10. Separate analyses were performed grouping driver mutations by biological pathways (per Ogawa 2019) and evaluating IPSS-M in isolation. Analyses were stratified by HMA-f or HMA-naïve (HMA-n). Results: The pooled dataset consisted of 80 patients (24 MDS-EB1, 43 MDS-EB2, 13 CMML; 56 males, 24 females) with a median age of 71 yrs (range 47-94). IPSS-M risk was Low in 2 patients (3%), Mod Low in 1 (1%), Mod High in 5 (6%), High in 21 (26%), and Very High in 51 (64%). 35% (28/80) of patients had prior HMA-f. The median number of treatment cycles was 3 (1-17). The ORR was 90% in HMA-n (47/52: 14 CR, 11 mCR + HI, 22 mCR) and 57% in HMA-f (16/28: 1 CR, 6 mCR + HI, 9 mCR). With a median follow-up of 12.4m, median OS was 28.2m in HMA-n and 8.3m in HMA-f. Median EFS was 17.9m in HMA-n and 5.5m in HMA-f. 25 (31%) patients went off protocol to receive allogeneic stem cell transplantation and 14 (18%) transformed to acute myeloid leukemia (AML). Factors significantly associated with ORR, OS, and EFS by UVA with a p value < 0.20 as well as factors that remained significant by MVA after backward selection (p < 0.10) are shown in table 1. Trisomy 8 was identified as a strong adverse factor for both OS and EFS in the HMA-naïve setting. When mutations were analyzed within pathways within the MVA, DNA methylation (OR 19.80, p=0.04) and chromatin modification (OR 25.6, p=0.04) were associated with improved ORR whereas RAS signaling (OR 0.02, p=0.05) was associated with worse ORR in HMA-f. RNA splicing (HR 0.40, p=0.073) was associated with improved OS in HMA-n. DNA methylation (HR 0.08, p < 0.01) and RNA splicing (HR 0.17, p=0.021) were associated with improved OS and RAS signaling (HR 37.9, p < 0.01) with worse OS in HMA-f. DNA methylation (HR 0.37, p=0.04) was associated with improved EFS and RAS signaling (HR 4.60, p < 0.01) with worse EFS in HMA-f. In a separate UVA, IPSS-M was associated with both OS (HR 2.83, p=0.06) and EFS (HR 3.24, p=0.02) in the HMA-f group. IPSS-M was not significantly associated with OS (HR 1.49, p=0.20) or EFS (HR 1.16, p=0.50) in the HMA-n group. Summary/Conclusion We identified clinico-molecular factors associated with treatment outcomes on HMA + VEN doublets in HR-MDS. These provisional findings are hypothesis-generating and should stimulate further work into the biology of venetoclax sensitivity in this patient population. Our findings are limited by patient numbers and relatively short follow-up time.Keywords: Myelodysplastic syndrome, Venetoclax